e pore.
What about the ligand gating? When calcium binds to the cystolic domain, it changes the cystolic domain's shape (its conformation), and the domain tugs on another linker chain connected to one of the pore-lining helices as it warps.
The channel's dynamics
In trying to clarify the effect of the mutation on BK channel function, Cui's group uncovered yet another mechanism for action at a distance.
After the mutation's discovery, experiments showed that it affects the pathway between a calcium-binding site on the cystolic domain called D367 and the channel's pore. The epilepsy-causing mutation is very close to the binding site but not part of it.
So how was the mutation making it easier to open the channel?
Cui wondered if it didn't have something to do with the mechanical properties of the amino acid that is substituted into the mutated form of the channel. The amino acid is glycine, which is exceptionally flexible; the presence of gylcine can allow a protein to bend at that position like a mechanical joint.
The scientists' idea was that this local flexibility might actually make the pathway between the D367 binding site and the pore more rigid, which in turn might make the channel more sensitive to calcium binding.
To see whether dynamics mattered, Cui's team immersed wild type channels in thick solutions of sugar or glycerol. The viscous solutions, which mimicked a more rigid D367 pathway, did indeed increase the channel's sensitivity to calcium.
To explore further, Cui's team then simulated the D367 pathway and its dynamics. The simulation showed that the wild-type protein is more flexible than the mutated protein and that glycine did indeed reduce the flexibility of other areas of the pathway.
The effect of the mutation, Cui concluded, was to make the D367 pathway move as a more rigid entity that couples the calcium binding site more tightly to the pore, so that it w
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| Contact: Diana Lutz dlutz@wustl.edu 314-935-5272 Washington University in St. Louis Source:Eurekalert |
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